Nusinersen offers only modest, if any, benefit in improving motor function for patients with spinal muscular atrophy (SMA) ― and it's associated with significant risks and adverse events, new research suggests.
Investigators retrospectively reviewed charts of 22 adult patients with type 2 and type 3 SMA and compared those who were treated with nusinersen with those who were untreated. All patients had disease of long duration, and most were wheelchair bound.
Although five patients in the treatment group reported subjective improvements, there was no significant motor gain or improved stability during the median 1-year follow-up, as measured by the percentage of change in Medical Research Council score (%MRC) of upper and lower limb strength.
Moreover, treated patients experienced serious side effects, including post–lumbar puncture headache, bacterial meningitis, and proteinuria.
"We think there is no dramatic improvement with nusinersen treatment, maybe only modest benefits, and it comes with its own risks that must be explained clearly to the patient," senior author Chafic Karam, MD, associate professor of neurology and director of the neuromuscular division, Oregon Health and Science University, Portland, told Medscape Medical News.
The findings were published online July 14 in Neurology.
The US Food and Drug Administration approved nusinersen, an antisense oligonucleotide that promotes expression of functional SNM protein, in 2016 after several studies showed that it improved motor function in infants and children.
"Following the approval, many [adult] patients felt strongly that they wanted to try it and give it a chance, even though there were no data in adults," Karam said. "We thought it might work because of its mechanism of action, which could in theory be helpful for all SMA types."
To investigate further, the researchers followed 22 adult patients between 2017 and 2019 and compared 10 participants who underwent treatment with nusinersen (median age, 33 years) with 12 who were not treated with the medication (median age, 34 years). Of these, nine patients had type 2 and 13 had type 3 SMA. Patients who received nusinersen were treated for 6 to 24 months (median, 12 months).
Of the 22 patients, 20 were nonambulatory, 17 had severe scoliosis, and 10 had severe respiratory impairment requiring ventilation.
To assess the degree of benefit in patients treated with nusinersen, the researchers calculated the sum of the MRC scores of upper and lower limb strength at baseline, then at 4 to 6 months, 1 year, and 2 years.
The outcome was change in %MRC, calculated as total MRC × 100 ÷ number of tested muscles × 5. The researchers also evaluated patients' subjective perceived functional gain.
Patients in the treated group showed modest changes in %MRC at 12 months and at 24 months (on average, 2.5% and 3.9%, respectively).
At 12 months, one patient who was in her early 20s showed improvement on the Hammersmith Functional Motor Scale.
Also at 12 months, one patient younger than 30 years endorsed muscle movement in her left arm, which "correlated with findings of new trace muscle contraction and movement with gravity eliminated in her left arm at 24 months," the investigators note.
At the same timepoint, three patients (two of whom were younger than 30 years) reported an increase in hand strength that resulted in improved maneuvering.
Among patients who were followed for up to 24 months, no significant change in grip strength on the handheld manometer was observed. Forced vital capacity, recorded in two patients after 12 months of treatment, remained stable.
Most patients in the untreated group had stable %MRC, although three showed a slight decline.
Salient safety findings regarding the treated group include the following:
Three patients required bone laminectomy for intrathecal access, and one patient developed bowel/bladder incontinence following the procedure.
Five patients experienced post–lumbar puncture headache, of whom two required a blood patch.
One patient contracted bacterial meningitis that required inpatient treatment and long-term antibiotics.
One patient died of respiratory failure (in the setting of pneumonia) shortly after treatment initiation.
Three patients discontinued treatment during the study period: one because of recurrent pneumonia and lack of improvement at 12 months, one because of lack of improvement after 24 months, and one because of proteinuria.
"The challenge, and we will never overcome this challenge, is that many centers and researchers are reporting their experience with nusinersen in adult patients," Karam noted. "A lot of studies are being published, and there will be many more.
"Although most say the drug is working and safe, you can never say a drug really works based on only observational studies without having a double-blind, randomized controlled trial with a placebo," he said.
This is because the placebo effect is high. Moreover, the more serious the disease, the higher the placebo effect will be, he added.
"People will be encouraged to treat more adult patients, but the question I ask is, at what cost? How much time, energy, invasive procedures are we doing? How many complications are we causing, and what are we getting in return?" Karam asked.
"First Do No Harm"
Commenting on the findings for Medscape Medical News, Colin Quinn, MD, assistant professor of clinical neurology, Hospital of the University of Pennsylvania, Philadelphia, said this was a "small but interesting study that suggests that adults may not benefit from nusinersen," as determined on the basis of strength (MRC) sum score.
The study "provides low-level evidence that nusinersen may be more harmful than helpful," noted Quinn, who was not involved with the research.
On the other hand, the study used a "very small dataset from which to draw substantial conclusions," he said.
Moreover, the total MRC score is "not a common or sensitive outcome assessment in SMA," Quinn added.
He noted that there are conflicting and limited data regarding the efficacy of nusinersen in adults with SMA.
"Until a larger-scale trial is performed with a placebo or delayed treatment arm, it will be very difficult to discern the value of nusinersen in this population," said Quinn.
In an accompanying editorial, Feza Daymeer, MD, associate professor, Department of Neurology, Istanbul University, Turkey, points to many "unanswered questions," including whether the benefit of nusinersen outweighs the risks.
The researchers "warned us of the potential serious problems and justifiably reminded us of the Hippocratic oath — Do not harm," Daymeer concludes.
Karam has served on advisory boards for Acceleron, Akcea, Alexion, Alnylam, Argenx, Biogen, CSL Behring, Cytokinetics, and Sanofi-Genzyme. Disclosurss for the other study authors are listed in the original article. Deymeer and Quinn report no relevant financial relationships.
Medscape Medical News © 2020
Cite this: High Risk, Low Benefit for Nusinersen in Adult SMA? - Medscape - Jul 27, 2020.